Available online at www.sciencedirect.com The Veterinary Journal The Veterinary Journal 174 (2007) 513–521 www.elsevier.com/locate/tvjl Review Molecular mechanisms of pathogenicity of Mycoplasma mycoides subsp. mycoides SC Paola Pilo 1, Joachim Frey *, Edy M. Vilei Institute of Veterinary Bacteriology, University of Bern, Langgass-strasse 122, 3012 Bern, Switzerland Accepted 13 October 2006 Abstract Mycoplasma mycoides subsp. mycoides SC, the aetiological agent of contagious bovine pleuropneumonia (CBPP), is considered the most pathogenic of the Mycoplasma species. Its virulence is probably the result of a coordinated action of various components of an antigenically and functionally dynamic surface architecture. The different virulence attributes allow the pathogen to evade the host’s immune defence, adhere tightly to the host cell surface, persist and disseminate in the host causing mycoplasmaemia, efficiently import energetically valuable nutrients present in the environment, and release and simultaneously translocate toxic metabolic pathway products to the host cell where they cause cytotoxic effects that are known to induce inflammatory processes and disease. This strategy enables the mycoplasma to exploit the minimal genetic information in its small genome, not only to fulfil the basic functions for its replication but also to damage host cells in intimate proximity thereby acquiring the necessary bio-molecules, such as amino acids and nucleic acid pre- cursors, for its own biosynthesis and survival. Ó 2006 Elsevier Ltd. Open access under CC BY license. Keywords: Mycoplasma mycoides subsp. mycoides SC; CBPP; Pathogenicity; Capsular polysaccharide; Lipoproteins; Adhesion factors; Variable surface proteins; Toxic metabolic pathway products; Catabolite repression 1. Introduction genetic resources and biosynthetic capacities, and adapt to an obligate parasitic lifestyle (Razin, 1997). Mycoplasma mycoides subsp. mycoides small colony The minimal cellular genome of mycoplasmas also type (SC) is the aetiological agent of contagious bovine serves as a blueprint for the design of synthetic live organ- pleuropneumonia (CBPP), a severe infectious disease of isms (Check, 2002). In contrast to other pathogenic bacte- cattle (Food and Agriculture Organization, 2003). Myco- ria, where virulence is determined mainly by toxins, plasma species are the smallest self-replicating organisms cytolysins and invasins, no such typical primary virulence currently found on our planet. Their genomes range from genes have been found on the genomes of the ten Myco- 580 kb for Mycoplasma genitalium (Fraser et al., 1995)to plasmas species that have been sequenced completely (Fra- 1358 kb for Mycoplasma penetrans (Sasaki et al., 2002), ser et al., 1995; Himmelreich et al., 1996; Glass et al., 2000; while that of M. mycoides subsp. mycoides SC has a size Chambaud et al., 2001; Sasaki et al., 2002; Papazisi et al., of 1211 kb (Westberg et al., 2004). This minimal genome 2003; Jaffe et al., 2004; Minion et al., 2004; Vasconcelos has led the Mycoplasma species to radically economise et al., 2005). Mycoplasmas seem rather to use intrinsic met- abolic and catabolic functions to cause disease in the affected host and to ensure the microbe’s survival (Abu- * Groun et al., 1994; Baseman and Tully, 1997; Razin, Corresponding author. Tel.: +41 31 631 2414; fax: +41 31 631 2634. 1997; Vilei and Frey, 2001; Pilo et al., 2005). Analysis of E-mail address: [email protected] (J. Frey). 1 Present address: Department of Microbiology, Columbia University data from a severe mycoplasmal pathogen, such as Medical Center, New York, USA. M. mycoides subsp. mycoides SC, is expected not only to 1090-0233 Ó 2006 Elsevier Ltd. Open access under CC BY license. doi:10.1016/j.tvjl.2006.10.016 514 P. Pilo et al. / The Veterinary Journal 174 (2007) 513–521 unravel the mechanisms of pathogenicity which lead to and efficient vaccines. While the total virulence of M. myco- CBPP, but may also be useful in the better understanding ides subsp. mycoides SC can only be determined by expen- of other pathogenic Mycoplasma species. sive experimental infections of cattle, which are difficult to CBPP is the only animal disease belonging to the A list justify ethically, the various individual molecular mecha- of most severe infectious animal diseases (as defined by the nisms that contribute to virulence, such as adherence, anti- World Organisation for Animal Health – Office Interna- genic variation, impact of capsular polysaccharides to tional des Epizooties, OIE) caused by a bacterium as a allow persistence and dissemination in the host, or cyto- transmissible agent. CBPP has the potential for very seri- toxic activity, can be studied by means of diverse in vitro ous and rapid spread across national borders. It is cur- immunoassays, cellular studies, or experimental mouse rently responsible for major losses in livestock production infection assays. in Africa and, therefore, has serious socio-economic conse- The recently established sequence of the complete gen- quences and is of major importance in the international ome of M. mycoides subsp. mycoides SC did not reveal trade of animals and animal products. In most other parts any primary virulence factors such as toxins or invasins of the world, CBPP was eradicated using drastic policies of (Westberg et al., 2004). Therefore, the molecular mecha- stamping out cattle in infected areas, control of cattle nisms of pathogenicity of M. mycoides subsp. mycoides movement, and quarantine (Turner, 1954, 1959). The re- SC, as well as of most other Mycoplasma species, are ‘‘hid- emerging outbreaks of CBPP in some European countries den’’ and require a consideration of the particularities of at the end of the last century demonstrated the constant metabolic pathways, surface antigens, and their regulation. threat of the disease to industrialized countries and The present review will give a short overview of the molec- required the re-introduction of expensive eradication mea- ular mechanisms of pathogenicity that have been unrav- sures (Egwu et al., 1996). elled to date and discuss their impact on the virulence of The basic requirements to control CBPP are highly effi- M. mycoides subsp. mycoides SC. In spite of the host spec- cient diagnostic tests that detect M. mycoides subsp. myco- ificity of M. mycoides subsp. mycoides SC, many basic ides SC not only in symptomatic animals but also in molecular mechanisms of virulence are also expected to asymptomatic carriers, together with vaccine strategies that be found in other Mycoplasma species. DNA sequence are able to reduce the infectious pressure in infected areas analysis has revealed that the genomes of mycoplasmas by preventing the pathogen from achieving host infection, consist of a minimal set of genes encoding the essential colonization, and multiplication (Thiaucourt et al., 1998; functions of life, which are conserved in most species and Thiaucourt, 2002). In this context, it is worth noting that subspecies. the live vaccines currently used to control CBPP in different regions of Africa were derived from strain T1 of M. myco- 2. Immunopathogenicity ides subsp. mycoides SC, which was developed in Tanzania in the 1950s. The efficacy of T1 vaccine strains have been The principal pathological consequence of M. mycoides evaluated on several occasions and they have shown subsp. mycoides SC infections is a massive inflammatory advantages but also drawbacks (Hubschle et al., 2002). reaction mainly restricted to the lungs of the affected cattle, For instance, cattle that were infected experimentally with leading to death by respiratory distress caused by lung con- strain T1/44 (or that were in contact with T1/44-infected solidation in up to 30% of cases (Provost et al., 1987; Food animals) developed severe lung lesions characteristic for and Agriculture Organization, 2003). In most infected cat- CBPP (Mbulu et al., 2004). Molecular analyses confirmed tle, however, CBPP is manifested in a chronic form, which the identity of re-isolated T1/44, therefore the observed allows the host to recover from disease but to remain a pathologies were attributed to this particular vaccine potential carrier of the pathogen and so a threatening res- strain. Furthermore, inactivated whole cell vaccines ervoir of M. mycoides subsp. mycoides SC (Provost et al., appeared to exacerbate the effects of CBPP in adult cattle; 1987; Food and Agriculture Organization, 2003). as a result there have been few challenges with inactivated Dedieu and collaborators (2005a) recently studied the vaccines (Nicholas et al., 2004). difference between the acute and chronic progression of To cause disease or to be virulent, M. mycoides subsp. CBPP in cattle at the molecular level. The authors per- mycoides SC possesses particular mechanisms to adhere formed a kinetic analysis of the response of cattle to an to the specific host tissue, to evade the host’s immune infection by M. mycoides subsp. mycoides SC and showed defence, to enable persistence and dissemination in the that in animals that recovered from disease, the CD4 infected animal, and to cause inflammation and disease Th1-like T-cell response to M. mycoides subsp. mycoides signs through cytotoxicity. The loss of any of these mech- SC was maintained over a long period (until slaughter of anisms can lead to attenuation or loss of virulence. Hence, the animals in the experiment). In contrast, in animals that a detailed knowledge of the molecular mechanisms of path- developed an acute disease, progression of the